PhPAd-DalPhos: Ligand-Enabled, Nickel-Catalyzed Cross-Coupling of (Hetero)aryl Electrophiles with Bulky Primary Alkylamines

Article abstract of DOI:10.1002/anie.201812862

The base metal-catalyzed C?N cross-coupling of bulky α,α,α-trisubstituted primary alkylamines with (hetero)aryl electrophiles represents a challenging and under-developed class of transformations that is of significant potential utility, including in the synthesis of lipophilic active pharmaceutical ingredients. Herein, we report that a new, air-stable Ni(II) pre-catalyst incorporating the optimized ancillary ligand PhPAd-DalPhos enables such transformations of (hetero)aryl chloride, bromide, and tosylate electrophiles to be carried out for the first time with substrate scope rivalling that achieved using state-of-the-art Pd catalysts, including room temperature cross-couplings of (hetero)aryl chlorides that are unprecedented for any catalyst (Pd, Ni, or other).

Full text of DOI:10.1002/anie.201812862

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Accepted Article
Title: PhPAd-DalPhos: Ligand-Enabled, Nickel-Catalyzed Cross-
Coupling of (Hetero)aryl Electrophiles with Bulky Primary
Alkylamines
Authors: Joseph Tassone, Emma England, Preston MacQueen,
Michael Ferguson, and Mark Stradiotto
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812862
Angew. Chem. 10.1002/ange.201812862
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PhPAd-DalPhos: Ligand-Enabled, Nickel-Catalyzed Cross-Coupling of
(Hetero)aryl Electrophiles with Bulky Primary Alkylamines
Joseph P. Tassone,[a] Emma V. England,[a] Preston M. MacQueen,[a] Michael J. Ferguson,[b] and Mark
Stradiotto*,[a]
Abstract: The base metal-catalyzed C-N cross-coupling of bulky
-trisubstituted
primary
alkylamines
with
(hetero)aryl
electrophiles represents a challenging and under-developed class of
transformations that is of significant potential utility, including in the
synthesis of lipophilic active pharmaceutical ingredients. Herein, we
report that a new, air-stable Ni(II) pre-catalyst incorporating the
optimized ancillary ligand PhPAd-DalPhos enables such
transformations of (hetero)aryl chloride, bromide, and tosylate
electrophiles to be carried out for the first time with substrate scope
rivalling that achieved using state-of-the-art Pd catalysts, including
room temperature cross-couplings of (hetero)aryl chlorides that are
unprecedented for any catalyst (Pd, Ni, or other).
Notwithstanding the utility of the Pd-catalyzed C-N cross-
coupling of NH substrates and (hetero)aryl (pseudo)halides (i.e.,
Buchwald-Hartwig amination, BHA[1]) en route to sought-after
(hetero)anilines, the use of Ni in place of Pd in such
transformations is attractive given the sustainability and cost
benefits,[2] as well as in terms of the favorable reactivity of Ni with
inexpensive and widely available (hetero)aryl chlorides.[3] The
most common approach employed in developing Ni-catalyzed C-
N cross-couplings[4] has involved the repurposing of ancillary
ligands that work well in BHA, with some well-established
bisphosphines[5] (e.g., dppf,[6] BINAP[7]) and N-heterocyclic
carbenes (e.g., IPr)[8] affording useful reactivity, primarily in
transformations of simple primary or secondary aliphatic/aromatic
amine coupling partners. However, the comparatively poor
performance of premiere BHA ligands,[9] including Buchwald’s
biarylphosphines,[10] suggests that new ancillary ligands tailored
specifically to the properties of Ni may prove advantageous in the
quest to address particularly challenging substrate pairings.
Despite such promise, ancillary ligand design targeted for use in
Ni-catalyzed C-N cross-coupling has remained essentially
unexplored.
Figure 1. State-of-the-art Pd and Ni catalyst systems for the cross-
coupling of bulky, primary amines (A and B), as well as the Ni pre-catalyst
system (C) reported in this work. Dipp = 2,6-diisopropylaniline.
modular design strategy has proven effective, with pre-catalysts
incorporating PAd-DalPhos and related variants enabling the Ni-
catalyzed monoarylation of ammonia,[11] unhindered primary
alkylamines,[11, 13] as well as primary amides and lactams,[14] with
a diversity of (hetero)aryl (pseudo)halides. These otherwise
challenging Ni-catalyzed C-N cross-couplings using PAd-
DalPhos ligands often proceed at room temperature, with
demonstrated substrate scope that is commonly competitive with,
or superior to, the best Pd catalysts reported to date.
Despite recent advances, metal-catalyzed C-N cross-
couplings involving ,,-trisubstituted primary alkylamines
remains
a
significant challenge. Such under-developed
transformations are appealing as a potential means of introducing
large hydrocarbon groups (e.g. adamantyl) into active
pharmaceutical ingredients to increase lipophilicity,[15] resulting in
changes in absorption or membrane permeability that can
positively modulate biological activity.[16] The groups of
Buchwald[17] and César[18] have disclosed what are state-of-the-
art Pd pre-catalysts incorporating tailored biarylmonophosphines
(L1 and L2) or backbone-decorated N-heterocyclic carbenes (L3
or L4) for the cross-coupling of (hetero)aryl halides with ,,-
trisubstituted primary alkylamines (Figure 1A). In each report,
ancillary ligand design was crucial in engendering the desired
reactivity, giving rise to useful (hetero)aryl electrophile (X = Cl ,
Br) scope at elevated temperatures (80-120 ºC),[17] or milder
reaction temperatures with primarily aryl (not (hetero)aryl)
chlorides (40-60 ºC).[18] Examples of analogous Ni-catalyzed
transformations are scarce, with reports from the groups of Tu,[19]
Montgomery,[20] Baran,[21] and Sawamura[22] each featuring one or
two entries whereby tert-butylamine and/or 1-adamantylamine is
employed, often with modest efficacy, in the context of a broader
Ni-catalyzed C-N cross-coupling survey. While Sawamura and
In 2016 we developed the bulky and modestly electron-
donating PAd-DalPhos[11] bisphosphine ligand featuring
a
phosphaadamantane donor fragment, which we envisioned would
work well in promoting rate-limiting C-N reductive elimination
within a presumptive Ni(0/II) catalytic cycle.[12] This new and
[a]
J. P. Tassone, E. V. England, P. M. MacQueen, Prof. Dr. M.
Stradiotto
Department of Chemistry
Dalhousie University
Halifax, Nova Scotia B3H 4R2 (Canada)
E-mail: mark.stradiotto@dal.ca
Dr. M. J. Ferguson
[b]
X-ray Crystallography Laboratory, Department of Chemistry
University of Alberta
Edmonton, Alberta T6G 2G2 (Canada)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201YXXXXX.
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10.1002/anie.201812862
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coworkers[23] have developed
a
polystyrene cross-linked
Table 1. Pre-catalyst screening and reaction optimization for the Ni-
catalyzed cross-coupling of 1a-c and 2a.[a]
bisphosphine (L5) that facilitates C-N cross-couplings of 1-
adamantylamine, tert-octylamine, and cumylamine with Ni(cod)2,
only 4-chlorotoluene or 4-chloroanisole are employed as
electrophiles, and elevated temperatures (120 ºC) are required
(Figure 1B). In this context, the Ni (or other base metal) catalyzed
C-N cross-coupling of ,,-trisubstituted primary alkylamines
and (hetero)aryl chlorides with synthetically useful substrate
scope has yet to be described in the literature. Herein, we report
that application of
a
new, air-stable Ni(II) pre-catalyst
incorporating the optimized ancillary ligand PhPAd-DalPhos
enables such challenging transformations (Figure 1C), including
the first examples of room temperature C-N cross-couplings of
,,-trisubstituted primary alkylamines and (hetero)aryl
chlorides by use of any catalyst (i.e., Pd, Ni, or other).
In the pursuit of a Ni catalyst capable of effecting C-N cross-
couplings of ,,-trisubstituted primary alkylamines, we
screened [(L)NiCl(o-tolyl)][24] pre-catalysts in the N-arylation of 1-
adamantylamine (2a) with three potentially challenging
(hetero)aryl chlorides (1a-c, Table 1) at 110 ºC. Pre-catalysts that
had proven effective in cross-couplings of less hindered primary
alkylamines with (hetero)aryl chlorides, namely C1[11] and C2[13a]
incorporating parent PAd-DalPhos (L6) and JosiPhos CyPF-Cy
(L7), afforded poor conversion to the target anilines 3a-c (entries
1 and 2). The dppf (L8) pre-catalyst C3 also did not afford
significant conversion to the desired products (entry 3), despite
effecting the cross-coupling of secondary alkylamines as
documented in prior reports.[25] Similarly, although C4 (featuring
CyPAd-DalPhos, L9) and C5 (featuring L10) are each known to
effect cross-couplings of cyclopropylamine,[13b] only C4 afforded
moderate levels of conversion in the case of 3a (68%) and 3b
(48%) (entries 4 and 5).
Temp
[°C]
110
110
110
110
110
110
110
80
Yield 3a
[%][b]
<5
<5
<5
68
<5
27
65
Yield 3b
[%][b]
11
<5
<5
48
8
27
83
Yield 3c
[%][b]
19
<5
<5
19
6
27
32
Entry
Pre-catalyst
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C7
C6
C6
C6
91
90
66
49
49
81
60
[a] Reaction conditions: pre-catalyst (5 mol%), NaO(t-Bu) (1.5 equiv), 1a-
c (0.12 mmol, 1.0 equiv), 2a (1.1 equiv), and toluene (1 mL, [ArCl] = 0.12
M) at the indicated temperature. [b] Conversions to product are estimated
on the basis of calibrated GC data.
On the basis of this initial screen, we anticipated that the
bulk of 2a might necessitate a less sterically hindered ancillary
ligand in order to improve catalytic performance. As such, we
sought to examine pre-catalysts containing PAd-DalPhos variants
in which the -P(o-tolyl)2 group was replaced with a -PPh2 or -P(i-
Pr)2 moiety (L11 and L12 respectively). While L11 and L12 are
known,[11] the corresponding [(L)NiCl(o-tolyl)] pre-catalysts (i.e.,
C6 and C7) had not been reported and were synthesized herein
as air-stable solids using a literature procedure.[11] Pre-catalysts
C6 and C7 exhibit spectroscopic and solid-state (Figure 2)[26]
features similar to those of PAd-DalPhos[11] and CyPAd-
DalPhos[13b] [(L)NiCl(o-tolyl)] pre-catalysts.
In screening C6 and C7 in the cross-coupling of 1a-c and
2a at 110 ºC (Table 1, entries 6 and 7), C6 afforded suitable
conversions to 3a and 3b, while only modest conversion to the
desired products was achieved using C7. In noting that C6
provided comparable or superior conversion to products versus
C4 in our test reactions at 110 ºC (entries 4 and 7), we examined
transformations with C6 at 80 and 60 ºC (entries 8 and 9). While
more mild reaction temperatures afforded improved conversion to
3a and 3c, lower conversion to 3b was noted under these
conditions. Additional screening to ascertain the effects of base
and solvent (see Tables S3-S9 of the SI for complete optimization
details) revealed the reagents and concentrations employed in
entry 9 of Table 1 to be generally most effective.
Figure 2. Single-crystal X-ray structures of C6 (left) and C7 (right; major
orientation of disordered tolyl group shown), each represented with thermal
ellipsoids at the 30% probability level. All hydrogen atoms, and the CH2Cl2
solvent molecule for C7, omitted for clarity. Selected interatomic distances
(Å): for C6, Ni–P1 2.2471(5), Ni-P2 2.1185(5), Ni-Cl1 2.2071(5), Ni–C42
1.9356(19); for C7, Ni–P1 2.1661(8), Ni–P2 2.2047(8), Ni–Cl1 2.1986(9),
Ni–C42A 1.943(4).
Having identified C6 as a promising pre-catalyst for the Ni-
catalyzed C-N cross-coupling of ,,-trisubstituted primary
alkylamines with (hetero)aryl chlorides, we then surveyed the
reaction scope (Scheme 1). (Hetero)aryl electrophiles featuring
electron-donating (3b,d), electron-withdrawing (3e,j-l) (e.g., ether,
fluoro, nitrile, and ketone functional groups), or ortho-substitution
(3c-d,i-j) were successfully employed. Cross-couplings
employing heteroaryl halides containing pyridine (3a,m),
quinoline (3f,n), benzodioxole (3g), benzothiophene (3h),
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10.1002/anie.201812862
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quinaldine (3o), and quinoxaline (3p) cores also proceeded
efficiently. Several sterically hindered, primary alkylamines could
be used, including 1-adamantylamine (3a-c,g-h), cumylamine
(3d,f,m-n), tert-octylamine (3e,l), and tert-butylamine (3i-k,o-p);
however, triphenylmethylamine proved unreactive under
analogous conditions. Our reported chemistry was shown to
function on gram-scale, with 1.049 g (95%) of 3p being produced
on a 5.5 mmol scale. While the majority of the transformations
featured in Scheme 1 focused on the use of synthetically
appealing (hetero)aryl chlorides, test cross-couplings involving
(hetero)aryl bromides (3f,k) and an aryl tosylate (3i) also proved
trisubstituted primary alkylamines when using C6, even at
elevated temperatures (Scheme 2B). Such chemoselectivity may
prove useful in sequential transformations, with C6 effecting
(hetero)aryl chloride C-N cross-coupling with an ,,-
trisubstituted primary alkylamine in the presence of a carbamate
functionality, followed by directed metalation[27] or the introduction
of
a second nucleophile in a subsequent cross-coupling
reaction[28] involving the carbamate moiety.
successful. However,
a
range of other phenol-derived
electrophiles (e.g. triflates, mesylates, or carbamates) were not
suitable coupling partners under analogous conditions. While
uncatalyzed SNAr chemistry seemed feasible in the formation of
3a, 3l, 3m, or 3p, <5% conversion (GC) to product was observed
in these transformations in the absence of C6. Notably, the first
room temperature C-N cross-couplings of ,,-trisubstituted
primary alkylamines with (hetero)aryl chlorides employing any
catalyst (Pd, Ni, or other) was achieved with a diverse set of
electrophiles (3i-p) when using C6.
Scheme 2. A. Exploring the effect of a carbamate additive on the Ni-
catalyzed cross-coupling of 1-chloronaphthalene and tert-butylamine. B.
Chemoselective cross-coupling reactions. C. Ni-catalyzed cross-coupling
of (hetero)aryl halides with other bulky nucleophiles. [a] Reaction
conditions: C6 (5 mol%), NaO(t-Bu) (1.5 equiv), 1i (0.12 mmol, 1.0 equiv),
2d (3.0 equiv), and toluene (1 mL, [ArCl] = 0.12 M). Conversion to 3i
determined on the basis of calibrated GC data. [b] Reaction conditions: C6
(5 mol%), NaO(t-Bu) (1.5 equiv), 1q-r (0.5 mmol, 1.0 equiv), 2a,d (1.1 or
3.0 equiv), and toluene (4.17 mL, [ArCl] = 0.12 M) at the indicated
temperature. Isolated yields reported. [c] Reaction conditions: NaO(t-Bu)
(1.5 equiv), 1 (0.5 mmol, 1.0 equiv), 5a-b (1.1 equiv), and toluene (4.17
mL, [ArCl] = 0.12 M). Isolated yields reported. [d] Conversion to 8b
determined on the basis of calibrated GC data.
Scheme 1. Scope of the Ni-catalyzed C-N cross-coupling of ,,-
trisubstituted primary alkylamines with (hetero)aryl electrophiles using
C6.[a] [a] Reaction conditions: C6 (5 mol%), NaO(t-Bu) (1.5 equiv), 1 (0.5
mmol, 1.0 equiv), 2a-d (1.1 or 3.0 equiv), and toluene (4.17 mL, [ArX] =
0.12 M). Isolated yields reported. [b] C6 (6 mol%). [c] Toluene (2.08 mL,
[ArCl] = 0.24 M).
We briefly explored the scope of other bulky nucleophiles
employing C6, beginning with hindered primary anilines (Scheme
2C). In such test transformations, electron-rich, electron-poor,
ortho-substituted, and heteroaryl electrophiles were C-N cross-
coupled successfully, including variants featuring benzothiophene
(7c) or quinoline (7d) motifs. Although these transformations
involving 2,6-dimethyl substituted anilines (7a-d) proceeded
efficiently at room temperature, the more hindered 2,6-
diisopropylaniline was not a suitable nucleophile, even at 110 ºC.
Challenging Ni-catalyzed C-O cross-couplings involving the
sterically hindered primary alcohols 3,3-dimethyl-2-butanol and
tert-butanol (affording 8a and 8b) proceeded efficiently under mild
conditions (60 ºC) when using C6. The only previous report of
Given that phenol-derived electrophiles such as (hetero)aryl
carbamates were unsuccessful coupling partners under our
optimized reaction conditions, we investigated whether these
were simply unreactive with catalytic intermediates derived from
C6, or if such substrates serve as catalyst poisons (Scheme 2A).
Addition of one equivalent of quinolin-6-yl diethylcarbamate (4) to
the otherwise successful (Scheme 1) room temperature cross-
coupling of 1-chloronaphthalene and tert-butylamine using C6 did
not hinder conversion to product 3i, suggesting that (hetero)aryl
carbamates do not inhibit catalysis. We exploited this reactivity
pattern in chemoselective cross-couplings of 1q and 1r, whereby
the aryl chloride group reacted preferentially with ,,-
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such transformations involving (hetero)aryl chlorides was recently
published by our group,[29] whereby C4 was used as a pre-
catalyst at 110 ºC. The superiority of C6 (>95%) over C4 (15%) in
C-O cross-couplings at 60 ºC (Scheme 2C) leading to 8b
suggests that C6 might hold promise in effecting other demanding
catalytic transformations under mild conditions.
In conclusion, we have developed a new Ni pre-catalyst
(C6) containing an optimized ancillary ligand PhPAd-DalPhos
(L11) that enables the cross-coupling of ,,-trisubstituted
primary alkylamines and related hindered nucleophiles with
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(hetero)aryl
electrophiles,
including
chemoselective
transformations. In addition to representing the first Ni-catalyzed
C-N cross-couplings of this type whereby the substrate scope is
competitive with that achieved by use of state-of-the-art Pd
catalysts, the use of C6 allows for unprecedented room
temperature C-N cross-couplings of ,,-trisubstituted primary
alkylamines and (hetero)aryl chlorides to be achieved. We
envision that the application of tailored PAd-DalPhos ancillary
ligands will continue to prove effective in solving outstanding
problems in base metal catalysis, and will report on our studies in
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Acknowledgements
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We are grateful to the NSERC of Canada (Discovery Grant for
M.S.; CGS-D for P.M.Q.; USRA for E.V.E.), the Government of
Canada (Vanier CGS for J.P.T.), the Killam Trusts, and Dalhousie
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for the donation of phosphatrioxaadamantane. We also thank Dr.
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[26] Complete experimental details and characterization data are provided
in the Supporting Information; CCDC 1877193-1877194 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
Keywords: amination • bisphosphines • cross-coupling • ligand
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Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Joseph P. Tassone, Emma V. England,
Preston M. MacQueen, Michael J.
Ferguson, and Mark Stradiotto*
Page No. – Page No.
PhPAd-DalPhos: Ligand-Enabled,
Nickel-Catalyzed Cross-Coupling of
(Hetero)aryl Electrophiles with Bulky
Primary Alkylamines
The incredible bulk: A new nickel(II) pre-catalyst featuring the PhPAd-DalPhos
ancillary ligand has been shown to be effective for the challenging cross-coupling of
sterically hindered primary alkylamines and (hetero)aryl halides under mild
conditions.
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